Aminomethylphenylbicyclononenols

ABSTRACT

Certain aminomethyl-9-phenylbicyclo(3.3.1)-non-3-en-9-ols and acid addition salts thereof as well as methods for their preparation are disclosed. These compounds exhibit analgesic and tranquilizer activity.

United States Patent 91 Schut [451 Feb. 13, 1973 [54]AMINOMETHYLPHENYLBICYCLONO NENOLS [75] Inventor: Robert Norman Schut,

sburg, Mich.

[73] Assignee: Miles Laboratories, Inc., Elkhart,

Ind.

22 Filed: Sept. 9, 1970 211 App]. No.: 70,884

Edward- [56] References Cited UNITED STATES PATENTS 3,108,998 10/1963Poos ..260/268 BC 3,l46,235 8/1964 Nichols ..260/268 PH 3,354,l6l11/1967 Schut ..260/268 BC OTHER PUBLICATIONS Gaylord Reduction withComplex Metal Hydrides lnterscience, 1956, p. 554-555.

Primary Examiner-Donald G. Daus Attorney-Joseph C. Schwalbach, Louis E.Davidson and Harry T. Stephenson 5 7] ABSTRACT Certainaminomethyl-9-phenylbicyco[ 3.3.1 ]-non-3 en-9-ols and acid additionsalts thereof as well as methods for their preparation are disclosed.These compounds exhibit analgesic and tranquilizer activity.

4 Claims, No Drawings SUMMARY OF THE INVENTION The compounds of thisinvention have the formula:

wherein R is 4-phenyl-l-piperazyl, diloweralkylamino in which the alkylgroup contains from one to four carbon atoms and N-methyl-N-phenethylamino and R is phenyl. When these compounds or theirpharmacologically acceptable acid addition salts are injectedsubcutaneously into an animal at a dosage of from 30 to 100 mg/kg ofbody weight, both analgesic and tranquilizing effects are observed.

These compounds can be readily prepared as shown by the followingequations where R and R are as previously defined:

COOH; C001 13 C l R-substltuted amine i R1 0H RlMgB! 3* if l LIALH;

R1 OH CHz-R Thus, the known carboxylic acid B is converted to the acidchloride C by refluxing with thionyl chloride. The solution isconcentrated under vacuum and the residue transformed to the ketoamide Dby reaction with the appropriate R-substituted amine in aqueous alkaliunder reflux conditions. This intermediate is then reacted with phenylmagnesium bromide in an inert solvent such as tetrahydrofuran to obtaincompound E which is reduced with lithium aluminum hydride to form thesubstituted aminoalcohol A as the free base which can be converted to anacid addition salt by reaction with such acids as hydrochloric,hydrobromic, maleic and the like in an inert solvent such as acetone,propyl alcohol or ethyl acetate. The precise conditions employedtoproduce the specific compounds encompassed within the scope of thisinvention are set forth in the examples which follow.

PREFERRED EMBODIMENTS OF THE INVENTION EXAMPLE 1 R is4-phenyl-1-piperazyl in formula A and R is phenyl A 1.8 gram (0.01 mole)sample of 9-oxobicyclo[3 '3.1] non-3-en-l-carboxylic acid (m.p. 134C.)was dissolved in 10 ml. of thionyl chloride and heated under reflux for30 minutes. The solution was concentrated under vacuum to yield 2.03grams of the corresponding carbonyl chloride as a yellow oil. A sampleof 57.9 grams of said chloride in 200 ml. of ether was added to astirred mixture of 50 grams (0.31 mole) of N-phenylpiperazine in 400 ml.of ether and 200 ml. of 20 percent aqueous sodium hydroxide solution.The addition was carried out rapidly enough to maintain reflux andstirring was continued thereafter at room temperature for 25 minutes.The organic layer which formed was separated, washed with water, driedand concentrated under vacuum. The syrupy residue was crystallized fromether to obtain 63 grams of l-(4-phenyl1-piperazyl)-carbonylbicyclo[3-3.1]non-3-en- 9-one as a white solidmelting at 127C. after recrystallization from aqueous isopropyl alcohol.

To a stirred solution of 5.71 grams (0.026 mole) of phenyl magnesiumbromide was added 6.48 grams (0.020 mole) of thel-(4-phenyl-l-piperazyl)carbonylbicyclo[3-3.1]non-3-en-9-one thusprepared in 150 ml. of dry tetrahydrofuran. The solution was stirredunder reflux for 3 hours and the organic salt was decomposed by addingammonium chloride solution. The solvent was evaporated, chloroform addedand the extract dried to yield a solid residue which afterrecrystallization from methanol-acetone weighed 7.32 grams and melted at193C. Upon analysis, this intermediate l-(4-phenyl-1-piperazyl)carbonyl-9-phenylbicyclo[3 -3.l lnon-3-en-9-olcontained 7.08 percent nitrogen compared to the calculated value of 6.97percent nitrogen.

To a suspension of 3 grams of lithium aluminum hydride in ml. oftetrahydrofuran was added 6.22 grams (0.015 mole) of the above preparedintermediate in 100 ml. of the same solvent and the mixture was stirredunder reflux overnight. The excess hydride was decomposed and aqueoussodium hydroxide solution was added until a precipitate formed. Thesolvent layer was separated and concentrated. The residue wasre-crystallized from ether to yield 5.33 grams (89 percent) of thedesired 1-(4-phenyl-1-piperazyl)methyl-9-phenylbicyclo[3-3.l]non-3-en-9-ol as a white solid which melted at 131C.and contained 7.20 percent nitrogen compared to 7.22 percent nitrogencalculated.

A 10-gram sample of the free base thus prepared was dissolved in 200 ml.of ethyl acetate and treated with 9.3 ml. of 2.77 normal HCl. Thehydrochloride was collected and recrystallized from methanol-ether toyield 7.19 grams of said salt melting at 251C.

EXAMPLE 2 R is dimethylamino in formula A and R is phenyl The reactionof 18 grams (0.094 mole) of the acid chloride prepared in Example 1 with8.47 grams (0.133

mole) of dimethylamine in ether and aqueous sodium hydroxide accordingto the method described in Example 1 resulted in the isolation of 16grams of ldimethylaminocarbonylbicyclo[ 3-3.1 lnon-3-en-9-one as aviscous oil which was reacted with phenyl magnesium bromide as set forthin Example 1 to produce a 97 percent yield of the corresponding amidealcohol melting at 180C. after recrystallization from aqueous acetone.Reduction of said amidealcohol with lithium aluminum hydride accordingto the procedure previously described in Example 1 produced the desired1- dimethyl-aminomethyl-9-phenylbicyclo[3'3.l ]non-3- en-9-ol in 73percent yield as a clear liquid boiling at 140C. at 2mm. pressure.Nitrogen found was 5.08 percent versus nitrogen calculated of 5.17percent.

Treatment of l l grams of the free base thus prepared with 4.6 grams ofmaleic acid in acetone produced the solid maleate which afterrecrystallization from acetone-ether melted at 156C.

EXAMPLES methyl-N-phenethylamino)methyl-9-phenylbicyclo[3'3.l]non-3-en-9-ol as a clear liquid with a boiling point of 210C. at0.5 mm. pressure. Crystallization of the distilled sample from ahydrocarbon fraction boiling at 30C. provided a white solid melting at76C. From this free base, the maleate was formed by reac tion of maleicacid in ethyl acetate and found to melt at 141C. The nitrogen content of2.94 percent corresponded to the calculated value.

By substituting the dimethylamine of Example 2 with otherdiloweralkylamines such as diethylamine, diisopropylamine anddi-n-butylamine, the corresponding compounds of formula A are producedin which R is diethylamino, di-isopropylamino and di-n-butylamino,respectively and R is phenyl.

What is claimed is: 1. A compound ot'the formula @CHr-R K on in which Ris phenyl, R is a member of the group consisting of4-phenyl-l-piperazyl, diloweralkylamino, and N-methyl-N-phenethyl-aminoand pharmaceutically acceptable acid addition salts thereof.

2. A compound as in claim 1 in which R is 4-phenyli-piperazyl and R, isphenyl.

3. A compound as in claim 1 in which R is dimethylamino and R is phenyl.

4. A compound as in claim 1 in which R is N-methyl- N-phenethylamino andR, is phenyl.

3 2 3 m re STATES PATENT ereicr QEHMQA'EE @F QGREQTWN 3 716 ,538 March 21973 Patent No. Dated lnventorosx Robert Norman Schut It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 3, line 28 "phenethylamino)carbonylbicycloi53'3.l] non-3en9-"should read phenethylamino)carbonylbicyclo [3.3.1]non-3-en-9- Claim 1,the structure and brackets appearing as should be deleted.

Signed and sealed this 3rd day of July 1973.

(SEAL) Attest:

EDWARD M.PLETCHER,JR. e Rene Tegtmeyer Attesting Officer ActingCommissioner of Patents

1. A compound of the formula
 2. A compound as in claim 1 in which R is4-phenyl-1-piperazyl and R1 is phenyl.
 3. A compound as in claim 1 inwhich R is dimethylamino and R1 is phenyl.